Bipolar (BP) disorder and schizophrenia (SZ) are devastating illnesses and are a major public health concern. Although these illnesses are separate diagnostic entities, they share many common clinical features and biological abnormalities. The two most consistent abnormalities observed in these illnesses are the abnormalities in the signal transduction mechanisms and the structural abnormalities in the brain. The two brain areas often implicated in these disorders are the prefrontal cortex (RFC) and the cingulate cortex. We are proposing a comprehensive study of phosphoinositide (PI) and Wnt signaling pathways in the prefrontal and cingulate cortex of postmortem brain samples obtained from subjects with BPdisorders, SZ and normal control subjects. This proposal is based on a central hypothesis that the abnormalities in the signaling mechanisms may be specifically due to abnormalities in some components of these signaling pathways and/or transcription factors activated by these pathways. Briefly, we plan to determine the protein and mRNA expression of phospholipase C (PLC) and protein kinase C (PKC) isozymes, IPs receptor subtypes, and myristoylated alanine-rich C kinase substrate (MARCKS), components of the PI signaling system. We will also determine the activity of PLC, PKC anc PKC-mediated phosphorylation of MARCKS. To examine the role ofthe Wnt pathway in these disorders, we will determine protein and mRNA expression of Disheveled, GSK-3P and p-catenin, all components of the Wnt signaling pathway, protein and mRNA expression and DNA binding of transcription factors, namely, CREB, AP-1 transcription factors (C-Jun and C-fos) in the PFC and cingulate cortex of BP and SZ subjects. These studies will provide comprehensive information if abnormalities in the major signaling pathways namely, PI and Wnt, are associated with the pathophysiology of BP and SZ. This may eventually lead to i better understanding of the pathophysiology of BP or SZ illnesses and may aid in the development of more appropriate therapeutic agents for the treatment of these disorders.